Lipid Drug Delivery Systems and Their Fate after Oral Administration

Abstract

A novel class of lipid formulation was investigated comprising GRAS (generally regarded as safe) materials. The formulations were all ‘surfactant-free’ (S-F) formulations, and also referred to as ‘Type IV’ lipid formulations. These formulations were isotropic, transparent, thermodynamically stable at room temperature and typically composed of > 50 % of mixed mono-, di- and triglycerides, > 30 % medium chain fatty acids oil and < 20 % hydrophilic co-solvent. At equilibrium, S-F formulations enhanced the solvent capacity of corticosteroids (log P > 3) and hydroxy benzoate derivatives over type II SEDDS and type III SEDDS, but generally were not superior solvents to mixtures of mono-, di- and triglycerides (Imwitor 988® and or Capmul MCM®) alone, for lipophilic steroids (log P < 3). In general, type III SEDDS which were composed of high hydrophilic content (hydrophilic surfactant, HLB > 1 2 , and hydrophilic co-solvent), were also better solvents for most steroidal compounds and hydroxy benzoate derivatives than type II SEDDS and type I SEDDS formulations. Surfactant with HLB > 12 inhibited lipolysis of MCT and mixed glycerides when the concentration of surfactant exceeded 40 % w/w. Hydrophobic surfactants (HLB < 10) did not inhibit lipolysis. Thus, the digestibility of dispersions formed by selfemulsifying systems would be dependent on the surfactants used and the quantity of TG available for lipolysis. Co-solvents did not appear to influence lipolysis, once the formulations had dispersed. Phase separation of lipid formulations following their dispersion in simulated intestinal fluid was studied. The lipid formulation behaviour was dependent on monoglyceride content. When sufficient monoglyceride (> 60 %w/v) was present demulsification and phase separation was noticed and was found to be dependent on the presence of phospholipid. This resulted in sedimentation of the phase rich V monoglyceride and water. The presence of triglyceride stabilised the formation of mixed micelles, which remained in a finely dispersed state. This unexpected phase separation is likely to have a considerable effect on the fate of drug dissolved in SEDDS formulations. The high concentrations of monoglyceride may be disadvantageous and could possibly result in precipitation of drug.

Date of Award	20 Nov 2002
Original language	English
Awarding Institution	University of Bath
Supervisor	Colin Pouton (Supervisor)